Toxicity evaluation of α-pyrrolidinovalerophenone (α-PVP): results from intoxication cases within the STRIDA project

Beck, Olof; Franzén, Lisa; Bäckberg, Matilda; Signell, Patrick; Helander, Anders

doi:10.1080/15563650.2016.1190979

Cited by 52 publications

(38 citation statements)

References 29 publications

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“…The enzyme velocities V enzyme (Equation 1) for the respective metabolic reactions were calculated at the median plasma levels of alpha-PVP at 64 ng/mL as published by Beck et al, 26 since no plasma concentrations of the investigated compounds could not be identified.…”

Section: Kinetic Studiesmentioning

confidence: 99%

Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

Manier

Richter

Schäper³

et al. 2018

Drug Testing and Analysis

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In vitro and in vivo experiments are widely used for studying the metabolism of new psychoactive substances (NPS). The availability of such data is required for toxicological risk assessments and development of urine screening approaches. This study investigated the in vitro metabolism of the 5 pyrrolidinophenone-derived NPS alpha-pyrrolidinobutyrophenone (alpha-PBP), alpha-pyrrolidinopentiothiophenone (alpha-PVT), alpha-pyrrolidinohexanophenone (alpha-PHP), alpha-pyrrolidinoenanthophenone (alpha-PEP, PV8), and alpha-pyrrolidinooctanophenone (alpha-POP, PV9). First, they were incubated with pooled human liver microsomes (pHLM) or pooled human liver S9 fraction (pS9) for identification of the main phase I and II metabolites. All substances formed hydroxy metabolites and lactams. Longer alkyl chains resulted in keto group and carboxylic acid formation. Comparing these results with published data obtained using pHLM, primary human hepatocytes (PHH), and authentic human urine samples, PHH provided the most extensive metabolism. Second, enzyme kinetic studies showed that the initial metabolic steps were formed by cytochrome P450 isoforms (CYP) CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 resulting in pyrrolidine, thiophene or alkyl hydroxy metabolites depending on the length of the alkyl chain. The kinetic parameters indicated an increasing affinity of the CYP enzymes with increase of the length of the alkyl chain. These parameters were then used to calculate the contribution of a single CYP enzyme to the in vivo hepatic clearance. CYP2C19 and CYP2D6 were mainly involved in the case of alpha-PBP and CYP1A2, CYP2C9 and CYP2C19 in the case of alpha-PVT, alpha-PHP, alpha-PEP, and alpha-POP.

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Section: Kinetic Studiesmentioning

confidence: 99%

Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

Manier

Richter

Schäper³

et al. 2018

Drug Testing and Analysis

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“…The method was successfully employed for routine drug testing and in the STRIDA project on NPS. A main conclusion was that dilution of urine with an internal standard solution is a viable and simple procedure for sample preparation, as has been advocated before, that can easily be automated. Another conclusion was that the high MS resolution offered by the Orbitrap technique is a key feature for providing highly accurate qualitative analytical information.…”

Section: Discussionmentioning

confidence: 99%

“…The LC–HRMS technology has also been crucial for the success of the STRIDA project on NPS, a collaboration between the Karolinska University Laboratory, Clinical Pharmacology and the Swedish Poisons Information Centre (Stockholm, Sweden), combining analytical and clinical data from intoxication cases presenting for emergency hospital care all over Sweden. This project first used a multi‐analyte LC–MS/MS method that was later replaced by an LC–HRMS method, mainly because of the non‐discriminative detection offered and the possibility to retrospectively search for new analytes after inclusion in the method. The number of analytes covered in the method increases continuously, as new substances are introduced on the NPS market.…”

Section: Introductionmentioning

confidence: 96%

Use of LC–HRMS in full scan‐XIC mode for multi‐analyte urine drug testing – a step towards a ‘black‐box’ solution?

et al. 2017

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The influx of new psychoactive substances (NPS) has created a need for improved methods for drug testing in toxicology laboratories. The aim of this work was to design, validate and apply a multi-analyte liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method for screening of 148 target analytes belonging to the NPS class, plant alkaloids and new psychoactive therapeutic drugs. The analytical method used a fivefold dilution of urine with nine deuterated internal standards and injection of 2 μl. The LC system involved a 2.0 μm 100 × 2.0 mm YMC-UltraHT Hydrosphere-C column and gradient elution with a flow rate of 0.5 ml/min and a total analysis time of 6.0 min. Solvent A consisted of 10 mmol/l ammonium formate and 0.005% formic acid, pH 4.8, and Solvent B was methanol with 10 mmol/l ammonium formate and 0.005% formic acid. The HRMS (Q Exactive, Thermo Scientific) used a heated electrospray interface and was operated in positive mode with 70 000 resolution. The scan range was 100-650 Da, and data for extracted ion chromatograms used ± 10 ppm tolerance. Product ion monitoring was applied for confirmation analysis and for some selected analytes also for screening. Method validation demonstrated limited influence from urine matrix, linear response within the measuring range (typically 0.1-1.0 μg/ml) and acceptable imprecision in quantification (CV <15%). A few analytes were found to be unstable in urine upon storage. The method was successfully applied for routine drug testing of 17 936 unknown samples, of which 2715 (15%) contained 52 of the 148 analytes. It is concluded that the method design based on simple dilution of urine and using LC-HRMS in extracted ion chromatogram mode may offer an analytical system for urine drug testing that fulfils the requirement of a 'black box' solution and can replace immunochemical screening applied on autoanalyzers. Copyright © 2017 John Wiley & Sons, Ltd.

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“…Some users have reported mental and behavioral disorders, such as hallucinating that people were hiding in walls, swimming toward a snow bank to hide from snipers, and breaking into a police station to seek safety . It is worth noting that α‐pyrrolidinovalerophenone (α‐PVP), one of the “second generation” of pyrrolidinophenones that belongs to the group of synthetic cathinones, has been found to be related to more cases of self‐injury, aggressive behavior, and suicidal ideations reported by emergency department staff and first responders . Several cases of death have also been associated with exposure to α‐PVP .…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11] It is worth noting that α-pyrrolidinovalerophenone (α-PVP), one of the "second generation" of pyrrolidinophenones that belongs to the group of synthetic cathinones, has been found to be related to more cases of self-injury, aggressive behavior, and suicidal ideations reported by emergency department staff and first responders. 12,13 Several cases of death have also been associated with exposure to α-PVP. [13][14][15][16][17][18][19][20] Considering the increase in the abuse of α-PVP, developing a sensitive method for its determination in biological samples is necessary.…”

Section: Introductionmentioning

confidence: 99%

Determination of synthetic cathinone α‐pyrrolidinovalero‐phenone and its metabolite in urine using solid‐phase extraction and gas chromatography–mass spectrometry

Cheng

Hsieh

Chen

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale The presence of α‐pyrrolidinovalerophenone (α‐PVP) and its metabolites in urine is evidence of the administration of α‐PVP. A toxicological challenge is that the metabolites of α‐PVP exhibit amphoteric properties, which make them unsuitable for detection using gas chromatography–mass spectrometry (GC/MS). In the study reported, proper derivatization and sample extraction were essential for improving the sensitivity for GC/MS analysis. Methods An automated solid‐phase extraction (SPE) method has been developed and optimized. The derivatization efficiency was tested using longer reaction time and the addition of polar pyridine into a mixture of N,O‐bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane. Method validation, including linearity, limit of detection, precision, accuracy, and recovery, was evaluated using automatic SPE and GC/MS. Results The results suggested that adding pyridine to BSTFA (1:1, v/v) significantly improved derivatization efficiency and precision. After optimization, the linear range was from 25 to 1000 ng mL−1 with R2 > 0.9950. The limit of detection was 5 ng mL−1 for α‐PVP and 25 ng mL−1 for OH‐α‐PVP. The recovery for SPE was over 88%. The inter‐day and intra‐day precisions were less than 15%. A forensic sample has been found containing α‐PVP (67.3 ng mL−1) and OH‐α‐PVP (560.2 ng mL−1). Conclusions This study is the first to validate an auto‐SPE‐GC/MS method for the quantification and qualification of α‐PVP and OH‐α‐PVP in urine. We have successfully improved the derivatization efficiency and developed a sensitive and semi‐automatic approach. This approach is desirable for the detection of synthetic cathinone at trace levels in biological samples.

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Toxicity evaluation of α-pyrrolidinovalerophenone (α-PVP): results from intoxication cases within the STRIDA project

Cited by 52 publications

References 29 publications

Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

Use of LC–HRMS in full scan‐XIC mode for multi‐analyte urine drug testing – a step towards a ‘black‐box’ solution?

Determination of synthetic cathinone α‐pyrrolidinovalero‐phenone and its metabolite in urine using solid‐phase extraction and gas chromatography–mass spectrometry

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